The TORC1 signaling pathway regulates respiration-induced mitophagy in yeast.
The TORC1 signaling pathway regulates respiration-induced mitophagy in yeast.
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DOI：
10.1016/j.bbrc.2018.05.123
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发表时间：
2018-07
影响因子：
3.1
通讯作者：
Yang Liu;K. Okamoto
中科院分区：
文献类型：
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作者：
Yang Liu;K. Okamoto
线粒体自噬是一种进化上保守的自噬过程，选择性地降解线粒体。这种分解代谢事件被认为是线粒体质量控制系统，对细胞稳态至关重要，然而，调节线粒体自噬的机制仍然很大程度上未知。本研究表明，TORC1 （targetofrapamycincomplex1）信号通路通过由Iml1、Npr2和Npr3组成的SEACIT （Seh1-associatedcomplexinhibitingTORC1）调控出芽酵母的有丝分裂。缺乏SEACIT的细胞在长时间的呼吸生长过程中表现出明显的自噬减少，而其他选择性自噬过程受到的影响较小。在相同的条件下，SEACIT突变体(1)用雷帕霉素（一种特异性TOR激酶抑制剂）处理，(2)缺乏Gtr1（一种刺激TORC1的Rag家族GTPase），(3)缺乏Pib2（一种磷脂酰肌醇3-磷酸结合TORC1激活剂）。值得注意的是，在缺乏Atg13的细胞中，Npr2的缺失加剧了线粒体自噬缺陷，Atg13是一种TORC1效应物，对自噬相关过程的激活至关重要，这表明TORC1下游还有其他线粒体自噬特异性调节因子。最后，我们发现npr2缺失的细胞不能稳定Atg32与Atg11的相互作用，Atg11是一种线粒体自噬必需的支架蛋白。总的来说，我们的数据表明seacit介导的TORC1信号失活是促进呼吸诱导的有丝分裂的关键步骤。
Mitophagy is an evolutionarily conserved autophagy process that selectively degrades mitochondria. This catabolic event is considered to be a mitochondrial quality control system crucial for cell homeostasis, however, mechanisms regulating mitophagy remain largely unknown. Here we show that the TORC1 (targetofrapamycincomplex1) signaling pathway regulates mitophagy in budding yeast via SEACIT (Seh1-associatedcomplexinhibitingTORC1) consisting of Iml1, Npr2, and Npr3. Cells lacking SEACIT displayed significant reductions in mitophagy during prolonged respiratory growth, while the other selective autophagy processes are less affected. Under the same conditions, mitophagy defects were strikingly rescued in the SEACIT mutants (1) treated with rapamycin, a specific TOR kinase inhibitor, (2) lacking Gtr1, a TORC1-stimulating Rag family GTPase downstream of SEACIT, and (3) devoid of Pib2, a phosphatidylinositol 3-phosphate-binding TORC1 activator. Notably, loss of Npr2 exacerbated mitophagy defects in cells lacking Atg13, a TORC1 effector crucial for activation of autophagy-related processes, suggesting additional mitophagy-specific regulator(s) downstream of TORC1. Finally, we found thatnpr2-null cells failed to stabilize the interaction of Atg32 with Atg11, a scaffold protein essential for mitophagy. Collectively, our data implicate SEACIT-mediated inactivation of TORC1 signaling as a critical step to promote respiration-induced mitophagy.